Macrophage-derived chemotactic factors and allergic asthma

Editorial Macrophage-derived allergic asthma

chemotactic

Human alveolar macrophages, presumably by virtue of low affinity receptors for IgE, have been activated by an IgE-dependent mechanism when they are properly sensitized and challenged.‘-” Chemotactic activities for neutrophils and/or eosinophils have been generated in vitro after activation of alveolar macrophages obtained from nonasthmatic subjects4. s and from asthmatic subjects described in the article by Gossett et al. in this issue of THE JOURNAL OF ALLERGYANDCLINICALIMMUNOLOGY, page 827. Physiologic relevance for these observations is suggested by the finding of sensitized alveolar macrophages in bronchoalveolar lavage fluid from atopic asthmatic subjects but not from normal nonatopic subjects. Alveolar macrophages from normal individuals, however, could be passively sensitized with sera from allergic individuals. Alveolar macrophages from atopic subjects without asthma were not examined. The implications of these observations for our understanding of the pathophysiology of asthma and the experimental details of their research manuscript entitled “Secretion of a Chemotactic Factor for Neutrophils and Eosinophils by Alveolar Macrophages from Asthmatic Patients” will be the focus of this discussion. The respiratory tract is exposed to foreign debris that continually impacts on its surface. Despite this assault the lung usually remains unaffected as a result of a variety of cleansing mechanisms. The cough mechanism expels aerosolized and mucus-entrapped material from large central airways. Cilia on the luminal side of pulmonary epithelial cells beginning at the level of terminal bronchioles beat in synchrony and direct the flow of mucus (along with substances caught in this viscous fluid) from the small peripheral airways to the bronchi, trachea, and pharynx. Secreted into this mucus layer one finds the different classes of antibodies with preferential appearance of IgA and perhaps IgE in atopic individuals. In the distal airways and alveoli reside the major phagocytic cellular constituent of lung defense, the alveolar macrophage. These cells are directly responsible for in-

Abhwvicc7ior7.s

SHETE: LT: PC: PAF:

factors

and

rtsd

Shydroxyeicosatetraenoic Leukotriene Prostaglandin Platelet activating factor

acid

gesting debris that reach the respiratory bronchioles and alveolar gas-exchange surface. Airborne particles, including allergens of less than 5 pm in diameter, reach these peripheral airways on inhalation.“-” Most pulmonary mast cells, eosinophils, and lymphocytes are found in the pulmonary tissue. Additional neutrophils and/or eosinophils accumulate under various pathologic inflammatory situations, indicating that elaboration of chemotactic activities by resident cells may be an essential element in the pathogenesis of pulmonary inflammation. Although a few mast cells apparently reside in the mucosa and at the air/ mucus interface,” most are separated from the lumen by a layer of epithelial cells and a basement membrane . The development of bronchoalveolar lavage has greatly facilitated studies of alveolar macrophages. Performance of this technique allows retrieval of respiratory cells from medium-size bronchi all the way out to alveoli in both animal and human subjects in a relatively noninvasive fashion.‘“* ‘I In all of the species studied, the alveolar macrophage comprises more than 90% of total cells in the normal airways. Approximately 4% to 8% of the remaining cells are lymphocytes, 1% to 2% are neutrophils, and about 0.4% are mast cells. Only rarely are eosinophils and basophils noted in cytologic preparations of cell suspensions from normal lavage material. Thus the alveolar macrophage is the principal resident cell in distal airways. When bronchoalveolar lavage is performed in human subjects with a variety of illnesses, it reveals alterations in the cell constituents. Increased numbers and percentages of lymphocytes are found in patients suffering from pulmonary sarcoidosis or hypersensitivity 777

778

Fowler and Schwartz

pneumonitis, of neutrophils in idiopathic interstitial tibrosis, and of eosinophils in asthmatic individuals, lo I’ Macrophages are capable of phagocytosis, mediator expression. and antigen processing. The lirst two activities are more germane to the current discussion Human alveolar macrophagcs ingest particulate m;~terials. foreign organisms. and immune complexes activities that are enhanced when C3h is deposited on the material to be ingested. Is I7 As a result the surface of peripheral airways is maintained sterile and relalively free of debris. Activation of human alveolar macrophages is obtained by invoking phagocytosis of particulate substances or by presentation of soluble agonists such as the calcium ionophore. A23 187. This results in generation of reactive oxygen intermediates. oxidation of liberated arachidonic acid via lipoxygc. nase (IXB,. 6trans LTB, Isomers. 5-HETE)‘” ” and cyclooxygenase (PGE,. PGF,., and thromboxane B,)” biochemical pathways. and release of ;I \.arictk of hydrolytic and proteolytic enrymes’” and chemo. tactic substances.‘. r, Release of these mediators IXIJ also occur when macrophages adhere to plastic. ‘. “‘I In the study under discussion, macrophage\ uerc suhjetted to a ‘Z-hour adherence phase. ” Becnusc actiLation by adherence requires much longer than 7 hr. these adherent cells expressed no appreciable chemotactic activity unless specificall! challenged Immunologic activation of macrophages by I&idependent perturbation of IgG Fc receptors is well accepted, I. 2:s-25 Marc recent Information indicates that low affinity receptors for IgE also reside in the plasma membrane of macrophages.“” Activation 01 IgE-sensitized macrophager with bivalcnt ant&n OI IgG anti-IgE has demonstrated that the >amc mecha. nism of receptor bridging required for immunologic initiation of mast cell acttvation” also occurs for macrophages.‘” Thus, release of neutrophil and cosinophil chemotactic activities by macrophages occurs through IgG- and IgE-mediated mechanisms. Characterization of these substances began some 7 to X Lr ago In one study at least two low-molecular-weight chemotactic factors for neutrophils wcrc elicited from IgG-activated normal human alveolar macrophages. ’ One WII~ a lipid of 400 to 800 MW, and another u’a\ ;I peptide of about IO,000 MW. The former material was probably LTB.,, which has IWU been biochemically characterized as the major lipoxygenase product (IS to 400 ngi I cy’ cells) generated by normal human alveolar macrophages stimulated with the calcium ionophore A23 187. Ix ?’ LTB, is cmc of the most potent factors for chemotaxis of neutrophils and eosinophils thus far described.g”, Z’ It also causes human peripheral monocytes but not human alveolar macrophages

to chemotax. ” Thus monocytes apparent]! iose thr’ll ihemotactic response to LTB, as they differentiarc, 111~.i\o into alveolar macrophages. L T’B, 1’. u>ua!l>. measured h) its specific clution protile when II i> \ui~ lccted to reverse-phase. high-performan<‘ ilyuil! c hromatopraph~ 111the presence 01‘ small ;unounts 11; ‘tuthentic “H-labeled I.TB,. Material clutiny III [ht. c‘OlTt‘C1 position IC then quantitied b\ i[s ultr-a\,ioi‘ 1 absorption spectra or by .I rrrdloilnlnLlnoass~1~ that I % rcasonabl\ specific till L’l’B, :I ii‘\\ potent chenl!? tactic metabolitc ot the 5-ltpoxygcnasc pathwa! i-HETE. ha\ been reported to hc gcneratcd IN human ;Ilveolar macrophages in lesser yuantitie\ !” In addition to LTB,. IgE-mediated actlvatlon ot human alveolar macrophages generates PAF activity PAF is a potent mediator of neutrophil chemotaxih. smooth muscle contraction, \asopermeability. vasodilation. and platelet aggregation. :I’) This factor is commonly quantified by aggregation of rabbit platelets and has been chemically defined as acetyl glyccryl cthcr phosphoq I choline The capacity ot’ human alveolar macrophages to produce the slow-reacting substances. I.TC, anti LTD ). appears lo be limited at best. One careful evaluation of’ A23 I87-stimulated human alveolar macrophages detected generation of LTB.,. 6-(ran> LTB, isomers. and 5HETE but no generatlon 01‘ LTC, or I.TI>,.l” The apparent lack of LTC, generation by human alveolar macrophages’” L’i i> in contrast to rodent alveolar macrophage?’ and human and rodent peripheral monocytes and peritoneal macrop,,ages:l’-: ” that generate appreciable quantities ;)I LTC,. Thus human macrophages apparently lose their capacity to generate lipoxygenase-mediated glow-rcacting substances as they differentiate into alveolar macrophages The report h\ GOWY ci al. I~I :hl, issue oi the JOUHN.\I examines the nature 01‘ the chemotactic substances zccretetl by macrophages obtained from their patients. The authors found three peaks of chemotactic activities with apparent molecular weight5 ranging from 3Otl to 1300 by gel filtration on Bio-Gel l?: none of which ~a.4 sensitive to proteases or hearlng. Chemotactic activity was also detected in the void volume of this column and should have a molecular weight more than 2000. This activitv was sensitive to proteasc digestion. indicating its protein nature. It was suggested that I,TB, NBS responsible for at least a portion of the low-molecular-weigh1 chemotactic activity because of the ability of purified LTBf to deactivate the chemotactic response ot healthy neutrophils to unfractionated secreted matcrial. However. a direct procedure with specificity and sensitivity to detect and quantify LTB,, PAF. and/or

Chemotactic factors and allergic asthma

VOLUME 74 NUMBER 6

other chemotactic mediators generated by these nacrophages is essential for establishing their presence. In summary, the possibility that human alveolar macrophages play a critical role in the airway hyperreactivity and bronchospastic response characteristic of atopic asthma is on the basis in part of the presence of allergen-specific IgE on macrophages obtained by bronchoalveolar lavage from subjects with allergic asthma. A similar study of alveolar macrophages in atopic subjects without asthma should be performed in order to determine whether the asthmatic response correlates specifically with IgE-armed macrophages. IgG-mediated pulmonary inflammation does not normally result in asthma, but more often alveolitis does, indicating that activation of macrophages alone may not be sufficient to cause asthma. Activation of resident alveolar macrophages by allergens may result in processing and ingestion of this allergenic material and may also result in the release of bronchospastic and cytotoxic mediators. PAF, for example, is generated by alveolar macrophages and is capable of directly producing bronchospasm. Release of reactive oxygen intermediates and proteolytic enzymes from these macrophages could damage the integrit) of the epithelial barrier. Such damage may also occur after release of chemotactic factors that attract eosinophils into the lung. Eosinophils have the capacity to damage epithelial tissue by release of the mediators found in their specific granules, including major basic protein, eosinophil cationic protein. and eosinophil peroxidase.“j Activated eosinophils also secrete the smooth muscle spasmogen LTC4.‘3fi Disruption of the pulmonary epithelial barrier sl-ould facilitate deposition of inhaled allergens in pulmonary tissue where contact with IgE-sensitized tissue mast cells would be optimal. The mast cell. by virtue of its high affinity receptors for IgE. is often considered the central cellular protagonist for initiation of an allergic asthmatic response. The association of bronchoconstriction after allergen inhalation with positive immediate skin reactions to the same allergens”‘, 3” further implicates an IgE-dependent mechanism involving mast cells. Indeed. human mast ccl1 mediators capable of causing bronchospasm include histamine, PGD?, LT(I* (a slow-reacting substance of anaphylaxis), and PI~F.“~ Tryptase. the major neutral protease in human mast cell granules. generates the anaphylatoxin, C3a, another smooth muscle spasmogen.Jn The diversity and magnitude of mast cell mediators capable of producing bronchospasm exceeds that from any other cell type. The localization of mast cells near brorchial smooth muscle, mucus secreting glands, and the epithelial basement membrane place it in a position to

779

exert a central role in the asthmatic response. However, mast cells in the airways are few in number compared to alveolar macrophages and may rarely contact inhaled allergens unless that allergen penetrates the mucus and epithelial barriers. The role played by the alveolar macrophage at the air/tissue interface in the relationship between itself, tissue mast cells, and eosinophils is an important concept to consider in terms of the pathogenesis and treatment of the asthmatic condition.

REFERENCES 1

2

Joseph M, Tonne1 AB, Capron A. Voisin C: Enzyme and superoxide anion production by human alveolar phages 40:416.

stimulated 1980

with immunoglobulin

Joseph

M. Tone1

AB,

Torpier

veniste J: Involvement processes of alveolar 3

release

platelet-activating

Merril WW, Naegel macrophagederived production 1980

1.

and partial

Hunninghake

GW,

B. Ben-

E in the secretory asthmatic patients. J

factor

2X8:1056, Dolovich

characterization.

Gadek

1973 MB, Killian aerosol

Bouffant

and

the specific

al-

J Clin

JE. Lawley

Inlest

TJ. Crystal

65:26X.

RG: Mech-

accumulation in the lungs of patients with fibrosis. J Clin Invest 6X:2.59. 19X1

LL,

Surprenant EL. Deposition airways. New Engl J Med

D. Wolff

PK. Obmin\ki

deposition

in chronic

mittent positive pressure breathing. Am Rev Respir Soler M.

( PAF-acether)

RA, Reynolds HY: Alveolar factor. Kinetics of in vitro

Wilson OF, Novey HS, Berke RA. of inhaled pollen extract in human

M: Pulmonary

x.

A. Amoux

when stimulated with Dis 125:70, 1982

GP, Matthay chemotactic

anisms of neutrophil idiopathic pulmonary 6.

G, Capron

Immunol

Clin Invest 71:221, 19X3 Amoux B, Simoes Caeiro MH, Landes A, Mathieu M. Durnux P. Benveniste J: Alveolar macrophages from asthmatic patients

5

E Clin Erp

of immunoglobulin macrophages from

LYSO-PAF-ACETHER lergen. Am Rev Respir 4.

release macro-

G. Newhouse bronchitis:

breathing techniques Dis I15:307. 1977

Charpin

J: Retention

inter-

verses

quiet

of pollen grains

in

human lung. Allergy 37:373. 1982 9. Guerzon GM, Pare PD. Michoud hl, Hogg JC: The number and distribution of mast cells in monkey lung. Am Rev Respir Dis I lY:59, 1979 IO.

Reynolds

HY,

Newball

HH:

Analysis

tory cells obtained from human Lab Clin Med X4:559. 1974

lung

of protein, by bronchial

and respiralavage.

II

Hunninghake GW, Gadek JE, Kawanami 0, Ferrans VJ. Cryatal RG: Inflammatory and immune processes in the human lung in health and disease: evaluation hy bronchoalvcolar lavage. Am J Pathol 97~149. I979

I2

Crystal Fulmer

RG. Roberts WC, Hunninghakc JD. Line RR: Pulmonary sarcoidosls:

GW. Gadek JE, a disease charac-

J

780

Fowler

rsrvrd I.7

and

Schwartz

and perpetuated

by actxatsd

lntcrn Med 94.73. 19x1 Reynold\ HY. Fulmer JD.

lunp ‘I -I!mphocyrc~

K.vm~ero~.sh~

I,\.

Frank MM, Crystal RG: Analy& ofccllular hronchoalveolar lavage tluld from pat&f\ pulmonary tibrosi\ and chronic Clan Inte%t 5Y:lh.s. lY77

16. Cohen

AR.

Clioc

K&en\

pnltem with

h! p+xvnsnivl1>

klJ. The human

al~col,n

Gad&.

JE.

Regularton trophll 1X. MarIm tricns

Hunninghakc

GW.

of the release

of alveolar

pncumonitl\

n~crophayc

Zimmerman

RI..

mrchanlsm

IO.

20

macrophapc\ Biochcm Biophy> 10x1’ Fe15 AU. Pawlo\cskl NA. C‘ramer

(r!slal

mllommation

Godartl

t’. Damon

Lewih KA. macrophape\.

KU

h) alrrotar

Commun

LB.

Kmg

I Oh.1 0X5.

‘Ik(‘.

Cohn

Michel

FB.

Corey

ingcbnon J Exp Med llH:lOOY. 1963 Hunnmghakr GW. Gadek JE. l-ale\ HM. macrophage-derived

phiI\ Stimuli hfx-17 4 I 080

25

M.

EJ.

lrukotriene B, producrion from Clin Res 3154X.A. 19X?

Daughada)

and

CC.

chemotacrlc

panial

.4mkr1

human

Douglas

SD:

Membrane

and human pulmonary dothcl Sot l9:37. lY76

alveolar

Reynolds HY. Atkinson tor\ for immunoglobulin

JP. Newhall Hti. and complement

macrophepes.

J Immunol

Cr)slal factors

characterization.

I IJ:lXl3.

receptors

I975

Kf’.

alveolar 01‘ macrcl10 particle

KG:

Human

for

ncum)-

J Clin

macrophages.

/.h.

leukorricnc

Cohn %A. Wiener E: The panlculare hydrolase\ phages II. Biochemical and morphological response

alveolar

24.

Kc; ncu

in the lung

IYR3 B, hmsynrhcci\

Scott WA: Human alveolar macrophagea produce 13,. Pm Nat1 Acad Ssi USA 79:7X66. IYX!

23.

1x11:1dnd tune

nlacrc,phagc-dcrl\ed

for amplifying

Am Rer Respir Dia 179’106. H\uch W. Sun FF: Irukotrlenc

22.

J

chemotactic factor i\m Rev Kcspir DIS I? I ‘2.:. I YX(I TR. AIrman I.C. Albert RK. Henderson \\‘R. Icuko 13, production by the human rllv~olar macrophagc. ;!

porentlat

2I

u’(‘.

c~mtenl UI Idiopathic

tlon. cuhi\‘ation in \‘ltro. ~md htudic\ of morphologic tion.rl characterlslic\ J Clin In\c\l 50: IJYO. IO’1 I7

:\rm

Invehl

on rahbil

J Reticuloen-

Frank MM: Recepon human alveolar